Summary: PD-1 axis blockers induce durable clinical responses in ~20% of patients with non-small cell lung cancer (NSCLC). However, most patients do not benefit from treatment and those who initially respond ultimately develop acquired resistance. There are limited treatment options for these clinical scenarios. To substantially reduce NSCLC mortality, it is imperative to: i) Identify novel biomarkers for optimal selection of patients for treatment; ii) Uncover immunotherapy targets beyond the PD-1/PD-L1 axis that may serve to treat patients with refractory tumors; and iii) Reveal the role of immunity during tumor progression to design early therapeutic interventions. Recent studies from our group identified baseline T-cell dysfunction and LAG-3 upregulation as key determinants for resistance to PD-1 blockade in NSCLC. We have also found that LAG-3 signaling induces T-cell apoptosis and identified FGL1 as major inhibitory LAG-3 ligand in cancer. We hypothesize that engagement of the LAG-3/FGL1 pathway mediates dominant immune evasion and T-cell dysfunction/death in a subset of NSCLCs insensitive to PD-1 therapies. In this project and through 3 complementary aims, we will leverage our expertise in cancer immunobiology and biomarkers to: i) Determine the biomarker value of measuring functional TIL profiles in human NSCLC; ii) Analyze the mechanisms and role of LAG-3/FGL1 interaction as immunomodulatory target in human lung malignancies; and iii) Examine the role LAG-3/FGL1 pathway and immune contexture in carcinogenesis and early lung cancer progression. The results from this work will accelerate translation of research concepts into the clinic for establishment of novel biomarkers, support interpretation of clinical trials and design optimal treatment modalities for early-stage and advanced lung cancer.